Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45, 47, 51-52 and 76-77 are currently pending in this application.
Election/Restrictions
Election was made with traverse of Group I, claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45 and 47, in the reply filed on June 25, 2026. The traversal is on the ground(s) that unity of invention under PCT Rule 13.1 exists because the cited art (Schlieve) fails to teach or suggest any method comprising contacting gut endoderm spheroids with both SM cells and ENCCs as the mesenchyme arise endogenously. This is not found persuasive for reasons of record because under a broadest reasonable interpretation “contacting” comprises inducing cells in a spheroid to become in contact with the recited cell type by any means, including as in forming contacts in situ and representing a cell mixture in a spheroid/organoid as in Schlieve (Fig. 1-3, pg. 887, left col.) or in Workman (Workman et al., Nat Med 23: 49-59 (2017)) as detailed in the anticipation rejection below. As explained below, Workman discloses contacting gut endoderm spheroids with both SM cells and ENCCs as a contacting mesenchyme arises endogenously in spheroid culture and comprises SM cells as evidenced by as evidenced by Takahashi and Spence and/or McCracken. The election/restriction is deemed proper and is therefore made final.
It is repeated that the product claims (e.g., claim 51) is interpreted as a product-by-process with no structural feature(s) recited or implied in these claims that would distinguish the claimed gastrointestinal organoid made by another process, e.g., without forming said cell mixture as recited, so long as the gastrointestinal organoid comprises the requisite epithelium, mesenchyme, and a functional enteric nervous system (ENS). Note, for patentability purposes product-by-process claims are treated paramountly as products, while, for patent infringement purposes, product-by-process claims are treated as process claims. See Abbott v. Sandoz, 566 F.3d 1282 (Fed. Cir. 2009). Thus in the instant case, unity of invention is not provided by reference back to the process claims (i.e., claim dependency) as the limitations of the process when not considered the same for the product claims as drafted.
Thus, restriction for examination purposes as previously indicated is proper because all the inventions listed in this action lack unity of invention for the reasons given above and previously set forth and claims 51-52 and 76-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45, and 47 have been considered on the merits.
Claim Objections
Claim 8 is objected to because of the following informalities: claim 8 appears to have a typographical error of “,,” in element c). Appropriate correction is required.
Claim Interpretation
In claim 1, the preamble phrase “from the three primary germ layers” is considered non-limiting as the claimed method is silent as to any step(s) comprising all three primary germ layers (see [0171]), rather the first step starts with a gut endoderm spheroid which may optionally be derived from a spheroid comprising the three primary germ layers or instead lacking any ectoderm, one of the primary germ layers. Here, the body of the claim fully and intrinsically sets forth all of the limitations of the claimed invention and the preamble phrase does not clearly provide any additional feature/step.
In claim 1, the term “gut organoid” is given its ordinary meaning in the art, which comprises intestinal organoids, colonic organoids, and gastric organoids, including subtypes such as fundic gastric, antral gastric, and esophageal organoids (Dedhia et al., Gastroenterology 150: 1098-112 (2016) at pg. 1 to pg. 2, para. 4; pg.3, 3rd para.; Fig. 2). Thus in claim 1, it is implied the cell mixture comprises undifferentiated cells from the cells of any of the spheroid, SM, and/or ENCCs that differentiate during the culturing to form more differentiated cells in the gastrointestinal organoid.
In claim 1, the term “functional” with regard to an “enteric nervous system (ENS)” is interpreted as means cells of enteric character (identifiable by known molecular markers) in a gastrointestinal organoid form a functional nervous system when at least some enteric neurons (ENS cells) form at least one network exhibiting electrical activity, neurotransmitter release and/or trigger smooth muscle contraction, regardless of the presence of any glia or ENS plexus (see instant Examples 2, 4, and 6; [0149]).
In claims 2-4, 8, 21 and 36, the term “derived” by its ordinary meaning in this context means the instant cells are derivatives from the named cell type from which they were derived, whether indirectly descending after one or more cell divisions (ancestral lineage) or directly, e.g., due to division-independent cell potency restriction, differentiation and/or maturation (such as terminal differentiation).
Claims 19-21 and 35-36 each recites wherein the gut endoderm spheroid is a “foregut” endoderm spheroid, which is interpreted as requiring foregut cells (such as determined by known marker expression (e.g., PGA4) but not necessarily excluding the presence of non-foregut cell types, e.g., midgut, hindgut, or posterior gastric cells or their progenitors, or any type of non-gastric cell. Further, claims 20-21 recite wherein the foregut endoderm spheroid is a “posterior” foregut endoderm spheroid which is interpreted as requiring posterior foregut cells (such as determined by known marker expression but not necessarily excluding the presence of non-posterior foregut cell types nor non-foregut cell types. Similarly, claims 35-36 recites wherein the gut endoderm spheroid is an “anterior” foregut endoderm spheroid, which is interpreted as requiring anterior foregut cells (such as determined by known marker expression but not necessarily excluding the presence of non-anterior foregut cell types, e.g., midgut, hindgut, or posterior gastric cells or their progenitors or non-gastric cells.
Claims 20-21 recite wherein the gastrointestinal organoid is a “gastric” organoid, which is interpreted as requiring gastric cells (such as determined by known marker expression) but not excluding non-gastric cell types, e.g., other gut cells. Similarly, in claims 21, 25 and 30 the terms “antral” and/or “fundic” is interpreted as requiring the organoid comprises antral and/or fundic gastric cells but not necessarily excluding other non-gastric gut cell types. Similarly, in claims 35-36 and 40, the term “esophageal” organoid is interpreted as requiring the organoid comprises esophageal cells but not excluding other non-esophageal gut cell types.
In claim 25, 30-31, 41 and 47, the terms CHAT+ (i.e., choline acetyltransferase “positive” or ChAT “positive”), TH+ (tyrosine hydroxylase or TH “positive”), ATP4B+, GIF+, αSMA+ TUJ1+, and FOXF1+ are each interpreted as meaning expressing a detectable amount of the named protein (e.g., CHaT, TH, TUJ1, etc., respectively), as determined by any method known in the prior art (Table 2, [0255]-[0258]). Similarly, in claims 25 and 30-31, the terms PDX1, MUC5AC, MUC6, gherlin, serotonin, histamine, gastrin, PGA3, CLDN18, and CDH17, are interpreted as meaning a detectable amount of the named protein as determined by any method known in the prior art, or lack thereof as recited in the claims. In claim 41, the term “TUJ1+ neuronal plexus” or “FOXF1+ mesenchymal layer” is interpreted as requiring some but not all cells of the plexus to be respectively TUJ1 protein “positive” or FOXF1 protein “positive.”
In claim 47, the phrase comprises “αSMA+ smooth muscle cells, enteric neurons and epithelium is interpreted with the modifier “αSMA+” only modifying the smooth muscle cells but not the entire list of nouns, i.e., not the enteric neurons and epithelium.
Claim Rejections - 35 USC § 112(a) - Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45, and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
The claims are directed to methods for producing a gastrointestinal organoid from gut endoderm spheroids by forming a mixture by contacting the spheroid with splanchnic mesoderm cells (SMCs or simply ‘SM’) and enteric neural crest cells (ENCCs), and culturing this mixture to form a gastrointestinal organoid(s) each having an epithelium, mesenchyme and an enteric nervous system.
Splanchnic mesoderm cells (SM) NOT derived from pluripotent stem cells
In view of dependent claim 2, the scope of all other claims are broad in that the methods as claimed encompasses wherein the spheroid, SM, and/or ENCC are not derived from pluripotent stem cells. While the prior art teaches gut spheroids and ENCCs can be obtained by methods not comprising pluripotent stem cell derivation, the prior art is silent as to obtaining isolated SM cells in vitro without derivation from a stem cell. Furthermore, the preamble regarding the three primary germ layers implies a pluripotent stem cell is employed at some point in the claimed methods.
The written description only provides wherein the SM are derived from human pluripotent stem cells and provide no guidance as to any other method of obtaining SM excluding using a pluripotent stem cell.
Gut endoderm spheroids and ENCCs are NOT contacted with gastric/esophageal mesenchyme cells
In view of dependent claim 6, the scope of claim 1 is broad in that the method as claimed encompasses wherein the method never comprises contacting the gut endoderm spheroids and ENCCs with gastric/esophageal mesenchyme cells. However, the cell mixture must eventually form a mesenchyme and the spheroids of the mixture must have gut endoderm (which may optionally comprise gastric/esophageal mesenchyme cells), and thus, any gastric/esophageal mesenchyme formed must be prevented from contacting all the ENCCs in the developing organoid, and similarly, upon the initial contacting, any added or endogenous ENCCs must somehow not come into contact with any with gastric/esophageal mesenchyme cells already present or forming in the endoderm spheroid. This issue is particularly problematic for claims 19-22, 25, 30-31,35-37, and 40-41 12 wherein the spheroid upon contacting specifically may include esophageal and/or gastric type cells as well as claim 12 at higher ratios (e.g., 2000 ENCCs per spheroid), such as specifically forming a gastric or esophageal organoid (respectively claims 21, 25 and 30 or 35-36 and 40).
The written description only provides wherein any differentiating gastric or esophageal mesenchyme cells in the developing spheroid/organoid arise spatial wherever they arise without any way to ensure no contact with ENCCs and which may already be present in the spheroid upon the ENCC contacting step. For example, the prior art teaches foregut spheroids/organoids comprising gastric mesenchymal cells (Broda et al., Nat Protoc 14: 28-50 (2019); IDS ref.).
Same pluripotent stem cells used to derive both the SM AND the ENCCs by contrasting steps (a)-(c)x2 (periods 1-5)
In view of dependent claim 12, the scope of claim 1 is broad in that the method as claimed encompasses wherein the method comprises using “the” pluripotent stem cells to derive both the SM, by steps a)-c) (periods 1-3), and the ENCCs by different steps a)-c) (periods 4-5) prior to the contacting step of claim 1. This requires sequential or interlaced performance of the 6 steps on the pluripotent stem cells to somehow produce both SM and ENCCs either together or sequentially from a single population of pluripotent stem cells subjected to all steps. There is no description for this method outside the claims and at [0010], which at 65. describes all of the above steps performed during the method without explanation. A detailed written description is only provided wherein the SM are derived from splanchnic mesoderm (Example 1) and the ENCC are derived from ectoderm in completely separate approaches (Example 2).
Mesenchyme capable of differentiating into αSMA+ smooth muscle cell
In view of dependent claim 31, the scope of claim 1 is broad in that the method as claimed encompasses wherein the method comprises differentiating a mesenchyme (tissue) into a single cell (αSMA+ smooth muscle cell). It is noted that singular and plural can be inferred by context and logic, here the wording clearly encompasses a single cell and instant [0261] does not define the use of singular/plural in the claims themselves. There is no description for such a method.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method: (1) wherein the SM are not derived from pluripotent stem cells, (2) wherein contact of the cells with gastric or esophageal mesenchyme cells is avoided throughout the entire method over the scope of the claims, (3) wherein every step of claim 21 is successfully performed on a single set of pluripotent stem cells, or (4) wherein the mesenchyme differentiates into a single cell. Adequate written description requires more than a mere statement of an intended result of practicing the invention and reference to the broadly claimed method described only at a high level of generality.
35 USC § 112(a), Scope of Enablement
Claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 45, and 47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while enabling for the methods of the claims wherein the gut endoderm spheroid is not gastric; the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to produce a gastric organoid comprising a mesenchyme capable of differentiating into a single αSMA+ smooth muscle cell.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
As noted in the written description rejection, the claims are broad in view of dependent claim 31 by encompassing wherein the method comprises differentiating a gastric spheroid’s mesenchyme (tissue) into a single cell (αSMA+ smooth muscle cell). It is noted that singular and plural can be inferred by context and logic, here the wording clearly encompasses a single cell and instant [0261] does not define the use of singular/plural in the claims themselves. There is no working example for such a method in the instant application nor in the prior art and the instant specification lacks any guidance or description of such a method, even prophetically. Thus, there is no evidence in the instant application or the prior art that the claimed methods could predictably accomplish the full scope claimed. Given the breath of the claims, lack of working examples and guidance provided in the specification, and lack of guidance and predictability in the prior art for such broad scope; undue and/or unreasonable experimentation would have been required for one skilled in the art to practice the method over the full scope claimed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45, and 47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 recites “gut endoderm spheroids” and differentiating a cell mixture comprising the aforementioned into a “gastrointestinal organoid,” which is incoherent, ambiguous and unclear as to which cells are differentiating and into what. Possible differentiation could occur within cells of the gut endoderm spheroids, SM and/or ENCCs while possible differentiations could proceed toward various cell progenitor types and terminal types, e.g., epithelial, mesenchymal, enteric neural cells, and/or other cell types of a gastrointestinal organoid. Furthermore, the term “gut endoderm spheroid” is not defined and under a broadest reasonable interpretation encompasses a broad genus including already formed esophageal organoids, gastric organoids, intestinal organoids, and colonic organoids, including subtypes such as foregut, posterior foregut, anterior foregut, midgut, hindgut, fundic gastric, antral gastric, and esophageal organoids. Thus, claim 1 paradoxically encompasses methods for preparing a gastrointestinal organoid by providing a gastrointestinal organoid (e.g., already comprising an epithelium, mesenchyme and functional ENS) and contacting it with the required cell types to make a mixture and culturing to “prepare” a gastrointestinal having ongoing cell differentiation of some kind but regardless already having the required organoid structures present before the contacting. Claims 2-4, 6, 8-9, 12, 16, 19-22, 25, 30-31, 35-37, 40-41, 45, and 47 are included in this rejection for depending from indefinite claim 1.
Claim 3 implies an additional active method step of “deriving” gut endoderm spheroids from definitive endoderm cells, such as by “differentiating” definitive endoderm cells into gut endoderm to spontaneously form the gut endoderm spheroids. Claim 3 is incoherent in the use of “and/or” as both alternatives entail deriving the gut endoderm spheroids from definitive endoderm cells, and thus the “and” seems redundant whereas a sole “or” would clearly provide for two alternative method steps, if that is the intent. Claims 4 is included in this rejection.
Claim 4 requires the definitive endoderm cells (already required to be derived from definitive endoderm cells) to also have been derived from pluripotent stem cells by an implied additional active method step of “deriving.” This is incoherent as to how the deriving is performed from two different parental cell types at once, such as encompassing wherein the definitive endoderm cells may be first converted to pluripotent stem cells and then derived into the definitive endoderm cells.
Claim 6 recites “gastric/esophageal,” which is not clear if what is before and after the slash forms a single limitation, recites an optional feature(s), or merely alternative combinations.
Claim 8 recites wherein “the pluripotent stem cells” are manipulated in deriving both SM and ENCCs, which is incoherent, ambiguous, and unclear for using the same antecedent pluripotent stem cells for both meaning the same cells have all the recited pathways activating in them and sequentially form SM and ENCCs or vice versa.
Claim 16 recites the relative phrase “low speed,” which is ambiguous and unclear as to the precise scope of the requisite speed that is “low,” which is neither defined in the claim or the instant specification. When there is no definition or standard for “low” versus not low, a person of ordinary skill in the art would not understand the metes and bounds of “low” speed centrifugation.
Claim 16 recites a “derivative” or “mimic” of an extracellular matrix, which is indefinite without definition or a standard means for discerning what material is derivative or mimic of an extracellular matrix and what is not. When there is no definition or standard for “derivative” versus not derivative or “mimic” versus not mimic, a person of ordinary skill in the art would not understand the metes and bounds of “derivative” or “mimic.”
Claim 25 recites the relative phrase “close proximity,” which is ambiguous and unclear as to the precise scope of the requisite proximity as “close” is not defined in the claim or the instant specification. When there is no definition or standard for “close” versus not close, a person of ordinary skill in the art would not understand the metes and bounds of “close” proximity.
Claim 31 recites a gastric organoid having about 50% or at least 50% mesenchyme, which is indefinite for lacking any defined measure of such a percentage, such as in terms of mass, area, molecular marker, etc.
Claim 41 depends from canceled claims 38 and 39, and thus is indefinite for failing to particularly point out and distinctly claim the subject matter.
Claim 47 recites a value and the alphabetical character ‘x’ in “50x, 150x, 200x,” etc., which is not defined by the claims nor even mentioned in the instant application. A person of ordinary skill in the art would not understand the metes and bounds of each of these alphanumeric terms, e.g., “about 50x, 150x, 200x,” etc. regarding grows in volume.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6, 12, 16, 45, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Workman (Workman et al., Nat Med 23: 49-59 (2017), IDS ref.) as evidenced by Takahashi (Takahashi et al., Cell Reports Methods 2(11): 100337 (2022), IDS ref.), Spence (Spence et al., Nature 470: 105-9 (2011), IDS ref.) and McCracken (McCracken et al., Nat Protoc 6: 1920-8 (2011), IDS ref.).
Regarding claims 1 and 3-4, Workman discloses a method (abstract) comprising contacting a gut endoderm spheroid (developing HIO) in culture with enteric neural crest cells (vagal NCCs) at day 16 (pg. 50, left col., last para.; Fig. 1a; pg. 57, right col., para. 2-3) wherein the spheroid comprises mesenchyme mesodermal cells in contact (i.e., a cell mixture spheroid with recombined ENCC) and continue culturing the spheroid to eventually form a gastrointestinal organoid (HIO) comprising an epithelium, gut mesenchyme, and a functional enteric nervous system (ENS) via migration and differentiation of the added ENCCs (Fig. 2; pg. 50, left col., 2nd para.; pg. 53, left col., para. 3-4; Fig. 4).
Although Workman does not expressly state the gut endoderm spheroid is contacted with splanchnic mesoderm cells (SM), as evidenced by Takahashi the Workman method produces FOXF1-expressing mesenchyme (marking SM and proximate precursors thereof) in the HIOs resulting from SM progenitor cells codeveloping with endoderm progenitors (pg. 5, Fig. 3G), the method comprising starting with culturing human pluripotent stem cells (H1 ESC) in mTesR1, using Activin A to induce definitive endoderm formation, using FGF and Wnt activation to induce gut endoderm spheroids from the definitive endoderm and finally 3D culturing in Matrigel in the presence of EGF to form HIOs (intestinal organoids) (Workman at Online Methods, Suppl. Fig. 1 and as cited therein, see e.g., Spence at pg. 108, last para., or McCracken at pg. 1922-1926, Fig. 1-3).
Regarding claim 2, Workman discloses the ENCCs are derived from pluripotent stem cells (at Online methods, pg. 1, para. 4).
Regarding claim 6, Workman is silent as to any contacting of the gut endoderm spheroid and ENCCs with a cardiac mesenchyme, septum transversum or esophageal mesenchyme.
Regarding claim 12, Workman discloses wherein a spheroid was contacted with 20,000–50,000 ENCCs (Online methods, pg. 1, para. 4)., which for spheroids less than 1-2 mm in diameter represents a ratio of at least about 1:1 to 1:2 by cell number. Note, where claimed ranges overlap ranges or values disclosed in the prior art, the claim may be anticipated (see MPEP 2131.03).
Regarding claim 16, Workman discloses wherein the ENCC contacting occurs with ENCCs in single-cell suspension and wherein the cell mixture (developing HIO) is cultured embedded in a 3D-matrix comprising the extracellular derivative Matrigel (at Online methods, pg. 1, para. 4).
Regarding claim 45, Workman discloses wherein the HIO is transplanted into a mammal (Fig. 2).
Regarding claim 47, Workman discloses HIOs in culture were 1-2 mm in diameter (e.g., after 7 weeks) but after transplantation and a 6-week duration can reach 5-6 mm, which is over about 50-fold (50x) (Fig. 2a, Fig. 4a; pg. 50, left col., last para.; Fig. 1a).
Thus, Workman as evidenced by Takahashi and Spence or McCracken anticipates the claimed invention.
Claims 1-4, 6, 8-9, 12, 16, 45, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Workman as evidenced by Takahashi and Spence or McCracken as applied above, and further as evidenced by Bajpai (Bajpai et al., Cell Death Differ 16: 807-25 (2009)).
Regarding claims 8-9, Workman discloses the ENCCs (vagal NCCs) were derived from pluripotent stem cells by a method comprising (b) culturing the neurospheres on a fibronectin extracellular matrix, and (c) collecting migrated neural crest cells as single cells (Workman at Online methods, pg. 1, para. 4; Suppl. Fig. 1d, 2; pg. 50, left col., 2nd para.). Regarding step (a), Workman teaches culturing the pluripotent stem cells in neural induction medium for 4 days and then adding retinoic acid from days 4-6 and references modifying methods of Bajpai (12), and as evidenced by Bajpai (cited therein), the method comprises (a) activating FGF and EGF pathways to form the neurospheres (free-floating rosettes or neuroectodermal spheres) for a period of 4-6 days (fourth period) (pg. 819, right col., 2nd para.). Note, where claimed ranges overlap ranges or values disclosed in the prior art, the claim may be anticipated (see MPEP 2131.03).
Claims 1-4, 6, 12, 16, 19-20, 31, 45, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Workman as evidenced by Takahashi and Spence or McCracken as applied above, and further as evidenced by Yu (Yu et al., Cell 184: 3281-98 (2021), IDS ref.).
Regarding claim 19-20, although Workman does not disclose their spheroids (developing HIOs) were foregut or gastric in nature; as evidenced by Yu, such spheroids comprise foregut and gastric precursor cells (in clusters c7 and c8) and develop into organoids having esophageal and gastric cells, as shown by the presence of GATA4+ SOX2+ cells and SOX2+ GATA4- cells as well as MUC5AC+ CLDN18+ cells (pg. 3285-3287, Fig. 4) with the spheroids/organoids made by the methods discussed above of McCracken and Spence (at e3, Human embryonic stem cells).
Regarding claim 31, Workman discloses the spheroids differentiating into organoids (HIO+ENS) having spontaneous contractile oscillations (phasic contractions) (Fig. 4b; pg. 53, left col., last para.).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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